Dronerarone Acts as a Selective Inhibitor of 3,5,3′-Triiodothyronine Binding to Thyroid Hormone Receptor-α1: In Vitro and in Vivo Evidence

Abstract

Dronedarone (Dron), without iodine, was developed as an alternative to the iodine-containing antiarrhythmic drug amiodarone (AM). AM acts, via its major metabolite desethylamiodarone, in vitro and in vivo as a thyroid hormone receptor α1 (TRα1) and TRβ1 antagonist. Here we investigate whether Dron and/or its metabolite debutyldronedarone inhibit T3 binding to TRα1 and TRβ1in vitro and whether dronedarone behaves similarly to amiodarone in vivo. In vitro , Dron had a inhibitory effect of 14% on the binding of T3 to TRα1, but not on TRβ1. Desethylamiodarone inhibited T3 binding to TRα1 and TRβ1 equally. Debutyldronedarone inhibited T3 binding to TRα1 by 77%, but to TRβ1 by only 25%. In vivo , AM increased plasma TSH and rT3, and decreased T3. Dron decreased T4 and T3, rT3 did not change, and TSH fell slightly. Plasma total cholesterol was increased by AM, but remained unchanged in Dron-treated animals. TRβ1-dependent liver low density lipoprotein receptor protein and type 1 deiodinase activities decreased in AM-treated, but not in Dron-treated, animals. TRα1-mediated lengthening of the QTc interval was present in both AM- and Dron-treated animals. The in vitro and in vivo findings suggest that dronedarone via its metabolite debutyldronedarone acts as a TRα1-selective inhibitor.